Quinazoline and medicaments containing these compounds

ABSTRACT

The invention relates to quinazoline derivatives corresponding to the following general formula   &lt;IMAGE&gt;   in which R is a mono- to trisubstituted 5-ring heterocycle from the group comprising triazoles, oxadiazoles, thiazoles and imidazoles, the heterocycle being attached to the piperazine or homopiperazine ring by a carbon atom, and n has a value of 2 or 3, or R represents an N-cyanophenyl imidocarbonate group, and to physiologically compatible salts thereof, to processes for their production and to medicaments containing these compounds.

DESCRIPTION

This invention relates to new quinazoline derivatives having anantihypertensive effect, to a process for their production and tomedicaments containing these compounds and, finally, to the therapeuticuse of these compounds.

An active substance from the class of quinazoline derivatives known as"PRAZOSIN" is already therapeutically used as an antihypertensivebecause it selectively blockades the α₁ -receptors without blocking α₂-receptors.

The object of the present invention is to provide new compounds havingimproved antihypertensive activity.

This object is achieved by the invention.

Accordingly, the present invention relates to new quinazolinederivatives corresponding to the following general formula ##STR2## inwhich: R is a mono- to trisubstituted 5-ring heterocycle from the groupcomprising triazoles, oxadiazoles, thiazoles and imidazoles, theheterocycle being attached to the piperazine or homopiperazine ring by acarbon atom, and n has a value of 2 or 3,

or

R represents an N-cyanophenyl imidocarbonate group, and tophysiologically compatible salts thereof. In general formula I, Rrepresents a mono- to trisubstituted 5-ring heterocycle, namely atriazole, oxadiazole, thiazole or imidazole, such as for example1,2,4-triazole, 1,2,4-oxadiazole, 1,3-thiazole and 1,3-imidazole.

The 5-ring heterocycle mentioned may be substituted 1 to 3 times, thedisubstitution being preferred in the case of the triazole ring and thethiazole ring. In the case of the oxadiazole ring and the imidazolering, the monosubstitution is preferred.

The substituents in question include, for example, the following groups:lower alkyl groups, lower alkoxy groups, carboxyalkyl groups andoptionally substituted, particularly lower-alkyl-substituted, aminogroups. Lower alkyl groups and unsubstituted amino groups are preferred.

In the context of the invention, "lower alkyl groups", "lower alkoxygroups" etc. are understood to be groups containing from 1 to 4 carbonatoms in the alkyl portion. Examples of groups such as these are methylgroups, ethyl groups and isopropyl groups, methyl and ethyl groups beingpreferred.

Thus, in general formula I for example, R is a 1,2,4-triazole ringsubstituted in the 3 position by an amino group which may optionallycarry linear or branched-chain lower alkyl radicals. One example of sucha group is the dimethylamino group.

In addition, R may be, for example, a 1,2,4-triazole ring substituted inthe 1 position by lower alkyl groups, preferably methyl or ethyl groups,and in the 3 or 5 position by an amino group which may optionally carrylinear or branched-chain lower alkyl radicals. A 1,2,4-triazole ringdisubstituted in the 1 and 3 positions of the aromatic heterocyclicsystem is preferred.

In addition, R may also represent, for example, a1,2,5-thiadiazole-1-oxide ring substituted in the 4 position by a loweralkoxy group, preferably a methoxy group or ethoxy group.

Where R is a 1,3-thiazole ring, this heterocycle may be substituted inthe 4 position by an amino group and in the 5 position by a carboxyalkylgroup, preferably a carboxyethyl group.

Finally, R may also represent the group ##STR3##

The present invention also relates to the physiologically compatiblesalts of these new quinazole derivatives.

These salts may be formed, for example, with mineral acids, such ashydrochloric acid, hydrobromic acid and hydriodic acid, phosphoric acid,metaphosphoric acid, nitric acid or sulfuric acid, or with organicacids, such as formic acid, acetic acid, propionic acid, phenyl aceticacid, tartaric acid, citric acid, fumaric acid, methane sulfonic acid,etc.

The present invention also covers all tautomeric forms and saltsthereof. The compounds according to the invention may form disalts andtrisalts and also hydrates which also fall within the scope of thepresent invention.

The compounds according to the invention are produced by a process whichis characterized in that

(a) to produce compounds corresponding to general formula I in which Rrepresents the group ##STR4## a compound corresponding to the followinggeneral formula ##STR5## in which n is as defined above, is reacted for80 minutes at 25° to 82° C., preferably at room temperature, withequimolar quantities of N-cyano diphenyl imidocarbonate corresponding tothe following formula ##STR6## in an alcohol, preferably in isopropanol,to form the compound of general formula Ia according to the invention##STR7## in which n is as defined above, or

(b) to produce compounds corresponding to general formula I, in which Ris a 1,2,4-triazole or 1,3-thiazole, a compound corresponding to generalformula Ia is reacted with a hydrazine derivative or mercaptoacetic acidester in an alcoholic solvent, preferably methanol, at refluxtemperature to form a compound of general formula Ic, Id, Ie or Ifaccording to the invention ##STR8## and in that the compound obtained insteps (a) or (b) is optionally converted into a physiologicallycompatible salt.

The compound of general formula I obtained is isolated in the usual way,for example by crystallization.

The compound of general formula I obtained may be converted into a saltin known manner using a pharmacologically compatible acid.

The compounds according to the invention, preferably in the form of asalt, may be formulated in any way for administration. Accordingly, theinvention also relates to medicaments containing at least one compoundaccording to the invention for use in human or veterinary medicine. Themedicaments according to the invention may be conventionally producedusing one or more pharmaceutically compatible carriers or diluents.

Accordingly, the compounds according to the invention may be formulatedfor oral, buccal and parenteral administration, oral administrationbeing preferred. For oral administration, the medicament may be present,for example, in the form of tablets, capsules, powders, solutions,syrups or suspensions which have been conventionally produced usingacceptable diluents. For buccal administration, the medicament mayassume the form of tablets or capsules which have been conventionallyformulated.

The compounds according to the invention may be formulated forparenteral administration by bolus injection or continuous infusion.Formulations for injection may be present in unit dose form as ampoulesor in multiple-dose containers with added preservative.

The medicaments may assume such forms as suspensions, solutions oremulsions in oily or aqueous carriers and may contain formulation aids,such as suspending agents, stabilizers and/or dispersants.Alternatively, the active principle may even be present in powder formfor reconstitution before use with a suitable carrier, for examplesterile, pyrogen-free water.

For oral administration, a suitable daily dose of compounds according tothe invention is from 1 to 4 doses containing a total of up to 1/3 mg-20mg per day, depending on the condition of the patient. In individualcases, it may be necessary to vary the dosage in dependence upon thereaction of the individual to the active principle or its formulationand upon the time at which or intervals at which it is administered. Forexample, there are cases where it will be sufficient to administer lessthan the minimum dose specified above, whereas in other cases the doseadministered will have to exceed the upper limit indicated.

The dosage for intravenous administration amounts to between about 1/5thand 1/10th of the oral daily dose.

Pharmacological Activity

The new compounds according to the invention are distinguished fromrecognized medicaments acting in the same direction by an improvement inthe pharmacological activity levels. This is reflected in the results ofthe comparative pharmacological tests described in the following.

A recognized method is to determine the blood-pressure-reducing effectin spontaneously hypertensive rats. The rats used had a starting weightof 160-185 g. Blood pressure was measured nonoperatively by means of aBP Recorder (type 8005, W+W electronic AG, Basel).

An average systolic blood pressure value of 125±6 mm Hg (n=10) wasrecorded in healthy rats (SIV 50, Dr. Ivanovas, Kisslegg, 160 to 180 g).The antihypertensive effect of the above-mentioned compounds wasexpressed in % taking the normal systolic value into account, a 100%effect signifying a reduction in blood pressure to the normal level of125 mm Hg.

Prazosin was used for comparison.

ED₅₀ (Prazosin): 0.7 mg/kg p.o.

ED₅₀ (Example 4): 0.17 mg/kg p.o.

The other Examples show similar pharmacological activities.

The invention is illustrated by the following Examples.

EXAMPLE 1N-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-tetramethylene-4-imino]-phenylisourea##STR9##

2.89 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazoline and2,38 g (10 mMoles) of N-cyanodiphenylimidocarbonate are suspended in 100ml of isopropanol and heated for 3 hours to 50° C. The reaction mixtureis then allowed to cool and the solids are separated off. Colorlesscrystals melting at 243° to 244° C.

Yield: 3.77 g (87%)

    ______________________________________                                        Rf: 0.64 (ethylacetate/ethanol 7:3)                                           C.sub.22 H.sub.23 N.sub.7 O.sub.3 (433)                                       .sup.1 HNMRdata:                                                                          δ = 3.50-4.13 (m)(2 × OC -H.sub.3 ;                   (d.sub.6 -DMSO, TMS as internal standard)                                                  ##STR10##                                                                    6.77 (s)(aromatic- -H) 1 H,                                                   7.03-7.63 (m)(aromatic- -H, N -H.sub.2) 8 H                       ______________________________________                                                    ppm.                                                          

EXAMPLE 23-ethoxy-4-[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)-piperazin-1-yl]-1,2,5-thiadiazole-1-oxide##STR11##

1.9 g (10 mMoles) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide are added to2.9 g (10 mMoles) of 4-amino-6,7-dimethoxy-2-piperazinoquinazolinedissolved in 50 ml of tetrahydrofuran and 10 ml of methanol, followed bystirring for 5 hours at room temperature. The solid accumulating isseparated off and recrystallized from 15 ml of dimethyl formamide and 10ml of ethanol.

Yellow crystals melting at 234°-235° C.

Yield: 3.01 g (70% of the theoretical)

    ______________________________________                                        Rf: 0.57 (ethylacetate/ethanol 70:30)                                         Cphd 18H.sub.23 N.sub.7 O.sub.4 S (433)                                       .sup.1 H--NMR spectrum:                                                                     δ =                                                                            1.43 (t) (C .sub.--H.sub.3 --CH.sub.2) 3 H,              (d.sub.6 -DMSO, TMS as                                                                             3.60-4.10 (m) (2 × N(C .sub.--H.sub.2).sub.2                            ;                                                        internal standard)   (2 × OC .sub.--H.sub.3) 14 H,                                           4.5 (q) (CH.sub.3 C .sub.--H.sub.2) 2 H,                                      6.77 (s) (aromatic- .sub.--H) 1 H,                                            7.13 (s) (--N .sub.--H.sub.2) 2 H (replaceable                                by D.sub.2 O)                                                                 7.47 (s) (aromatic- .sub.--H) 1 H ppm.                   ______________________________________                                    

EXAMPLE 34-amino-2-[4-(3-amino-1H-1,2,4-triazol-5-yl)-piperazin-1-yl]-6,7-dimethoxyquinazoline##STR12##

4.33 g (10 mMoles) ofN-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-tetramethylene-4-imino]-phenylisoureaare dissolved with 0.5 g (10 mMoles) of hydrazine hydrate in 20 ml ofmethanol and the resulting solution heated for 20 minutes to relfuxtemperature. After cooling to room temperature, the reaction solution isconcentrated in vacuo. The residue is recrystallized from methanol.

Colorless crystals melting at 172° to 173° C. (decomp.).

Yield: 2.94 g (79% of the theoretical)

    ______________________________________                                        Rf: 0.65 (methanol/                                                           NH.sub.3 --conc. 99:1)                                                        C.sub.16 H.sub.21 N.sub.9 O.sub.2 (371)                                       .sup.1 H--NMR-spectrum:                                                                   δ =                                                                            3.27 (m) (--N(C .sub.--H.sub.2).sub.2) 4 H,                (d.sub.6 -DMSO, TMS as                                                                           3.63-4.00 (m) (N(--C .sub.--H.sub.2).sub.2) 4 H,           internal standard) 3.80 (s) (--OC .sub.--H.sub.3) 3 H,                                           3.85 (s) (--OC .sub.--H.sub.3) 3 H,                                           5.63 (s,broad) (N .sub.--H.sub.2) 2 H (replaceable                            by D.sub.2 O)                                                                 6.78 (s) (aromatic- .sub.--H) 1 H,                                            7.12 (s,broad) (N .sub.--H.sub.2) 2 H (replaceable                            by D.sub.2 O)                                                                 7.47 (s) (aromatic- .sub.--H) 1 H,                                            11.57 (s,broad) (N-- .sub.--H) (replaceable                                   by D.sub.2 O) ppm.                                         ______________________________________                                    

EXAMPLE 44-amino-2-[4-(5-amino-1-methyl-1H-1,2,4-triazol-5-yl)-piperazin-1-yl]-6,7-dimethoxyquinazoline##STR13##

This compound is produced as in Example 3 from 4.33 g (10 mMoles) ofN-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-tetramethylene-4-imino]-phenylisoureaand 0.4 g (10 mMoles) of methyl hydrazine.

Colorless crystals melting at >280° C.

    ______________________________________                                        Rf: 0.32 (EtOAc/MeOH 50:50)                                                   C.sub.17 H.sub.23 O.sub.2 N.sub.9 (385).1/2 H.sub.2 O                                          Calc: C 51.78 H 6.59 N 31.98                                                  Found: C 51.80 H 6.18 N 31.54                                .sup.1 HNMRspectrum: (d.sub.6 -DMSO, TMS as internal standard)                                  ##STR14##                                                                    3.33 (s)(NC -H.sub.3) 3 H,                                                     ##STR15##                                                                    3.80 (s)(OC -H.sub.3) 3 H,                                                    3.83 (s)(OC -H.sub.3) 3 H,                                                    6.00 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    6.77 (s)(aromatic- -H) 1 H,                                                   7.10 (s, broad)(N -H.sub.2) 2 H                                               (replaceable by D.sub.2 O)                                                    7.47 (s)(aromatic- -H) 1 H, ppm.                             ______________________________________                                    

EXAMPLE 54-amino-2-[4-(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)-piperazin-1-yl]-6,7-dimethoxyquinazoline##STR16##

This compound is produced as in Example 3 from 4.33 g (10 mMoles) ofN-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-tetramethylene-4-imino]-phenylisoureaand 0.46 g (10 mMoles) of methyl hydrazine. After the reaction solutionhas been concentrated, the compound is obtained by fractionalcrystallization from ethanol/methanol (3:1).

Colorless crystals melting at 250° to 252° C.

    ______________________________________                                        Rf: 0.59 (CHCl.sub.3 /ethanol.NH.sub.3 [3.3 m]8:2)                            C.sub.17 H.sub.23 N.sub.9 O.sub.2 (385)                                                       Calc: C 52.98 H 6.02 N 32.71                                                  Found: C 53.07 H 6.00 N 32.61                                 .sup.1 HNMRspectrum: (d.sub.6 -DMSO, TMS as internal standard)                                 ##STR17##                                                                    3.50 (s)(NC -H.sub.3) 3 H,                                                     ##STR18##                                                                    3.77 (s)(OC -H.sub.3) 3 H,                                                    3.81 (s)(OC -H.sub.3) 3 H,                                                    5.00 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    6.77 (s)(aromatic- -H) 1 H,                                                   7.13 (s, broad)(N -H.sub.2) 2 H                                               (replaceable by D.sub.2 O)                                                    7.47 (s)(aromatic- -H) 1 H ppm.                               ______________________________________                                    

EXAMPLE 64-amino-2-[4-(4-amino-5-carbethoxythiazol-2-yl)-piperazin-1-yl]-6,7-dimethoxyquinazoline##STR19##

4.33 g (10 mMoles) ofN-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-tetramethylene-4-imino]-phenylisourea,1.6 ml (14.8 mMoles) of thioglycolic acid ethyl ester and 20 ml oftriethylamine are heated under reflux for 7 hours in 20 ml of methanol.After the reaction solution has cooled to room temperature, the reactionproduct is filtered off under suction and recrystallized from acetone.

Colorless crystals melting at 189° to 190° C.

Yield: 3.72 g (81% of the theoretical)

    ______________________________________                                        Rf: 0.52 (CH.sub.2 Cl.sub.2 /CH.sub.3 OH 90:10)                               C.sub.20 H.sub.25 N.sub.7 O.sub.4 S (450)                                                  Calc:   C 52.28 H 5.48 N 21.34                                                Found:  C 52.38 H 5.47 N 21.32                                   .sup.1 H--NMR-spectrum:                                                                    δ =                                                                             1.20 (t) (CH.sub.3 --C .sub.--H.sub.2) 3 H,              (d.sub.6 -DMSO, TMS as                                                                             3.53 (m, broad) (--N(C .sub.--H.sub.2).sub.2) 4 H,       internal standard)   3.67-3.97 (m) (N(--C .sub.--H.sub.2).sub.2) 4 H,                              3.77 (s) (OC .sub.--H.sub.3) 3 H,                                             3.83 (s) (OC .sub.--H.sub.3) 3 H,                                             4.08 (q) (CH.sub.3 C .sub.--H.sub.2) 2 H,                                     6.77 (s, broad) (aromatic- .sub.--H),                                         N .sub.--H.sub.2) 3 H                                                         (replaceable by D.sub.2 O                                                     7.13 (s, broad) (--N .sub.--H.sub.2) 2 H                                      (replaceable by D.sub.2 O)                                                    7.47 (s) (aromatic- .sub.--H) 1 H ppm.                   ______________________________________                                    

EXAMPLE 74-amino-2-[4-(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)-homopiperazin-1-yl]-6,7-dimethoxyquinazoline##STR20##

4.47 g (10 mMoles) ofN-cyano-[(4-amino-6,7-dimethoxyquinazolin-2-yl)-N,N-pentamethylene-4-imino]-phenylisoureaare dissolved with 0.46 g (10 mMoles) of methyl hydrazine in 20 ml ofmethanol and the resulting solution heated for 5 hours to refluxtemperature. After cooling to room temperature, the reaction solution isconcentrated in vacuo. The residue is purified by column chromatographyon silica gel (eluent:CHCl₃ /triethylamine in EtOH 3.3 molar).

Light yellow crystals melting at 128° to 132° C.

    ______________________________________                                        Rf: 0.58 (CHCl.sub.3 /triethylamine in EtOH [3.3 m]70:30)                     C.sub.18 H.sub.25 N.sub.9 O.sub.2 (399)                                       .sup.1 HNMRspectrum:                                                                          δ = 1.92 (m)(C -H.sub.2) 2 H,                           (d.sub.6 -DMSO, TMS as internal standard)                                                      ##STR21##                                                                    3.38 (s)(C -H.sub.3) 3 H,                                                      ##STR22##                                                                    3.77 (s)(OC -H.sub.3) 3 H,                                                    3.83 (s)(OC -H.sub.3) 3 H,                                                    4.87 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    6.73 (s)(aromatic- -H) 1 H,                                                   7.03 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    7.43 (s)(aromatic-  -H) 1 H ppm.                              ______________________________________                                    

EXAMPLE 84-amino-2-[4-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-homopiperazin-1-yl]-6,7-dimethoxyquinazoline##STR23##

This compound is produced as in Example 7. The end product is purifiedby column chromatography as described in Example 7.

Light yellow crystals melting at 208° C. (decomp.).

    ______________________________________                                        Rf: 0.37 (CHCl.sub.3 /triethylamine in EtOH [3.3 m]70:30)                     C.sub.18 H.sub.25 N.sub.9 O.sub.2 (399)                                       .sup.1 HNMRspectrum:                                                                          δ = 1.90 (m)(C -H.sub.2) 2 H,                           (d.sub.6 -DMSO, TMS as internal standard)                                                      ##STR24##                                                                    3.30 (s)(C -H.sub.3) 3 H,                                                     3.80 (s)(OC -H.sub.3) 3 H,                                                    5.83 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    6.67 (s)(aromatic- -H) 1 H,                                                   7.04 (s)(N -H.sub.2) 2 H                                                      (replaceable by D.sub.2 O)                                                    7.33 (s)(aromatic- -H) 1 H ppm                                ______________________________________                                    

We claim:
 1. Quinazoline derivatives corresponding to the followingformula ##STR25## in which: R represents a triazole ring which issubstituted in the 1-position by a methyl group and in the 3-position orthe 5-position by an amino group, the triazole ring being attached tothe piperazine or homopiperazine ring through a carbon atom, and n has avalue of 2 or 3,and physiologically compatible salts thereof. 2.4-amino-2-[4-(3-amino-1-methyl-1H-1,2,4-triazol-5-yl)-piperazin-1-yl]-6,7-dimethoxyquinazolineand physiologically compatible salts thereof. 3.4-amino-2-[4-(5-amino-1-methyl-1H-1,2,4-triazol-3-yl)-piperazin-1-yl]-6,7-dimethoxyquinazolineand physiologically compatible salts thereof.
 4. A medicament containingan antihypertensive effective amount of a compound as claimed in claim 1together with an inert pharmaceutically compatible carrier or an inertpharmaceutically compatible diluent.
 5. A medicament containing anantihypertensive effective amount of a compound as claimed in claim 2together with an inert pharmaceutically compatible carrier or an inertpharmaceutically compatible diluent.
 6. A medicament containing anantihypertensive effective amount of a compound as claimed in claim 3together with an inert pharmaceutically compatible carrier or an inertpharmaceutically compatible diluent.